Abstract
Background: Obesity is associated with impaired vascular function. In the cardiovascular system, protease-activated receptor 2 (PAR2) exerts multiple functions such as the control of the vascular tone. In pathological conditions, PAR2 is related to vascular inflammation. However, little is known about the impact of obesity on PAR2 in the vasculature. Therefore, we explored the role of PAR2 as a potential link between obesity and cardiovascular diseases.Methods: C57BL/6 mice were fed with either a chow or a 60% high fat diet for 24 weeks prior to isolation of aortas. Furthermore, human coronary artery endothelial cells (HCAEC) and human coronary smooth muscle cells (HCSMC) were treated with conditioned medium obtained from in vitro differentiated primary human adipocytes. To investigate receptor interaction vascular endothelial growth factor receptor 2 (VEGFR2) was blocked by exposure to calcium dobesilate and a VEGFR2 neutralization antibody, before treatment with PAR2 activating peptide. Student's t-test or one-way were used to determine statistical significance.Results: Both, high fat diet and exposure to conditioned medium increased PAR2 expression in aortas and human vascular cells, respectively. In HCSMC, conditioned medium elicited proliferation as well as cyclooxygenase 2 induction, which was suppressed by the PAR2 antagonist GB83. Specific activation of PAR2 by the PAR2 activating peptide induced proliferation and cyclooxygenase 2 expression which were abolished by blocking the VEGFR2. Additionally, treatment of HCSMC with the PAR2 activating peptide triggered VEGFR2 phosphorylation.Conclusion: Under obesogenic conditions, where circulating levels of pro-inflammatory adipokines are elevated, PAR2 arises as an important player linking obesity-related adipose tissue inflammation to atherogenesis. We show for the first time that the underlying mechanisms of these pro-atherogenic effects involve a potential transactivation of the VEGFR2 by PAR2.
Highlights
Obesity is associated with comorbidities such as type 2 diabetes and cardiovascular diseases (CVD) (Despres, 2012)
To determine whether the observed changes in aortic protease-activated receptor 2 (PAR2) expression were related to AT, we analyzed the effect of Conditioned media (CM) from murine adipose tissue explants on Human coronary smooth muscle cells (HCSMC)
We demonstrated that PAR2 activation and subsequent effects involved a transactivation of the vascular endothelial growth factor receptor 2 (VEGFR2)
Summary
Obesity is associated with comorbidities such as type 2 diabetes and cardiovascular diseases (CVD) (Despres, 2012). During the progress of obesity AT undergoes modulation such as the enlargement of adipocytes, Abbreviations: AT, Adipose tissue; BMI, Body mass index; CM, Conditioned media; COX2, Cyclooxygenase 2; CVD, Cardiovascular disease; FCS, Fetal calf serum; GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; HCAEC, Human coronary artery endothelial cells; HCSMC, Human coronary smooth muscle cells; HFD, High fat diet; PAR2, Protease-activated receptor 2; PAR2-AP, Proteaseactivated receptor 2 activating peptide; SEM, Standard error of the mean; VEGF, Vascular endothelial growth factor; VEGFR2, Vascular endothelial growth factor receptor 2; VEGFR2-NA, Vascular endothelial growth factor receptor 2 neutralizing antibody. A switch in the secretome toward a prominent release of pro-inflammatory adipokines (Ouchi et al, 2011). It has been proposed that high levels of circulating pro-inflammatory adipokines found in diseases such as obesity and type 2 diabetes mellitus have an impact on cardiovascular function (Greenberg and Obin, 2006). We explored the role of PAR2 as a potential link between obesity and cardiovascular diseases
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